# US 5,703,236 A · Tetrahydrofuran antifungals

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- Number: US 5,703,236 A
- Document ID: US5703236A
- Status: Granted
- Kind: A
- Application number: 08/458,551
- Filed: 1995-06-02
- Granted: 1997-12-30
- Earliest claimed: 1993-12-21
- Assignees: Schering Corporation
- Inventors: Anil K. Saksena; Viyyoor M. Girijavallabhan; Raymond G. Lovey; Russell E. Pike; Haiyan Wang; Yi-Tsung Liu; Ashit K. Ganguly; Frank Bennett
- Web page: https://patentgrep.com/patent/US5703236A

## CPC

- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/10: Antimycotics
- C07D 233/56: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

A compound represented by the formula I ##STR1## wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl; R.sub.1 is a straight or branched chain (C.sub.3 to C.sub.8) alkyl group substituted by one or two hydroxy moieties, an ether ester (e.g., a polyetherester or phosphate ester) thereof or a pharmaceutically acceptable salt thereof and pharmaceutical compositions thereof useful for treating and/or preventing fungal infections are disclosed.

## Claims

### Claim 1

A method of making compounds of the formula I ##STR112## wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl, and wherein the absolute stereochemistry at each asterisk carbon (*) is same i.e., S,S or R,R substantially free of S,R or R,S and wherein S or R-lactic acid ester is contacted with pyrrolidine and a hydroxy protecting group reagent converted into the corresponding lactic acid amide, which is selectively reduced to the corresponding propionaldehyde and then converted into the corresponding N-formylaminopropanimine which comprises:
(a) reacting the N-formylaminopropanimine of the formula II ##STR113## with ethylmagnesium bromide under Grignard reaction conditions sufficient to produce a compound of the formula III ##STR114## wherein the absolute stereochemistry induced at the double asterisk carbon (**) is substantially the same as that at the single asterisk carbon and wherein PG is a hydroxy protecting group and (b) reacting the compound of formula III with a compound of formula IV ##STR115## in the presence of 1,8-diazabicycloundec-7-ene and at elevated temperatures for a time sufficient to produce the compound of formula V ##STR116## and (c) reacting the compound of formula V with a catalytic amount of Pd black on carbon in the presence of formic acid to produce after purification the compounds of formula I.

### Claim 2 (depends on 1)

A method of claim 1 wherein S-lactic acid methyl ester is used as the starting material and the Grignard reaction is conducted in the presence of more than one equivalent of bis(trimethylsilyl)acetamide.

### Claim 3 (depends on 1)

A method of claim 1 wherein R-lactic acid methyl ester is used as the starting material and the Grignard reaction is conducted in the presence of more than one equivalent of bis(trimethylsilyl)acetamide.

### Claim 4 (depends on 1)

The method of claim 1 wherein the compound of formula IV is represented by the formula. ##STR117##